Previously we discovered that herpes simplex type 1 (HSV-1) enters laboratory cell lines by endocytosis as well as by nonendocytosis mechanisms. HSV-1 enters monkey kidney (Vero) cells by direct penetration of the plasma membrane, while the virus enters Chinese hamster ovary (CHO) cells that express virus entry receptors by pH-dependent endocytosis. HSV-2 infects persons through mucosal surfaces or through breaks in keratinized squamous epithelial cells and then travels to the nervous system where the virus establishes latency in neurons. We have found that HSV-1 enters primary and transformed epidermal keratinocytes through endocytosis, while the virus enters primary neurons and neuroblastoma cell lines by penetration of the plasma membrane. Entry of the virus in keratinocytes is inhibited by agents that inhibit inhibit endocytosis such as drugs that elevate the pH of endosomes or inhibit cellular tyrosine kinase activity. These same drugs do not inhibit entry of the virus in transformed neuronal cells.